Medicinal monoazo compounds



Patented Feb. 18, 1936 UNITED STATES PATENT OFFICE MEDICINAL MONOAZO COIWPOUNDS No Drawing. Application October 19, 1933, Serial No. 694,340

6 Claims.

to processes for making the same.

Although many amino aromatic compounds and their derivatives are known to have physiologlcal action, they are generally not used for medicinal or therapeutic purposes, because of their toxicity, and also because they are oxidizable in the human body to para-hydroxyl derivatives. These para-hydroxyl derivatives, even though of decreased toxicity, and even though they retain in large part the physiological action of the compounds from which they were derived, do not function satisfactorily because of the toxicity of the para-hydroxyl grouping. These phenolic hydroxyl groups readily enter into combinations including sulfonic or glucuronic ,acid groupings, which are inert and inefiective from a physiological viewpoint.

For example, it was early found that compounds such as aniline a-nd acetanilide (Schmiedeberg, Archiv fiir experimentelle Pathologie und Pharmakologie, vol. 8, page 1, 1878) are oxidized to para-amino phenols in the human system, which last-mentioned compounds are eliminated from the system in the form of inert and ineffective combinations.

Ithas long been thought necessary, in order to decrease the toxicity and also to prevent the formation of such para-hydroxylated compounds, to insert a substituent group in thepara-position in such amino-aromatic derivatives. According to this theory, phenacetin and a large number of other para compounds have been developed and have achieved wide spread utilization in the field of medicine.

We have now found, however, that it is possible to obtain certainorthoand/or meta-halogen and/ or alkyl substituted azotized aromatic amines of markedly decreased toxicity and enhanced therapeutic value, without regardto whether or not the para-group was substituted.

These amines are preferably produced by the diazotization and coupling of a meta and/or ortho halogen and/or alkyl substituted aromatic amine with a diamino aromatic compound, such as metaphenylenediamine. The preferred orthoand/or meta substituents include chlorine, bromine, io-

- phenylene-diamine in acid solution.

dine, methyl, ethyl, propyl, butyl, amyl, ethylene, propylene, butylene, etc. It is desirable to exclude certain substituent groups such as the sulphonic acid group, the alkoxy group and the hydroxy group, from these compounds.

These compounds are not particularly toxic, whether or not they are substituted in the paraposition; are not converted into inert compounds even though they may contain hydroxyl groups; and are particularly of value because of their J enhanced bactericidal action, and because of their elimination in the urine.

The probable structural formula of the preferred type of the metaand/or ortho-halogen and/or alkyl substituted azo compounds of the 35 present invention is as follows:

' N Hg in which either R and/or R may represent a. halogen atom as Cl, Br, F, I, or an alkyl group, as, for example, CH3, CzHs, C4H9, C5H11, and so forth.

The preferred method of obtaining these compounds is by diazotizing the orthoand/ or metahalogen and/or alkyl substituted anilin and coupling the corresponding diazonium salt with m- The dyes obtained are of similar character, and form from yellow to dark brown crystals, slightly soluble in water, very soluble in organic solvents such as methanol, ether, acetone, car-' bon tetrachloride, and toluene. For purification, they may be recrystallized out of toluene.

By recrystallization out of toluene, as well as certain other organic solvents not miscible with water such as ligroin, the compound may be pre- 1 pared devoid of certain particular undesirable impurities, particularly phenolic bodies arising during diazotization.

With acids, they form salts, the hydrochlorides being dark red to bluish violet colored crystals. 45 These salts are soluble in water, from which solution 'the bases may be precipitated with an alkali. The hydroxide, carbonate, or acetate of analkali metalmay be used as the alkali for this purpose. I 2- J 50 indicator. was adde'd'toaso1utionof'5E8 g. of m phenylene- "diamine hydrochloride in "100 cc. of water 2-methylaniline (o-to1uidine),- when diazotized and coupled with "m-phenylenediamine, forms clusters of orange-colored needles, which, when recrystallized out of toluene, have a melting point of about 98-99 C. v

The probable structural formula of this compound is:

l NH: CH;

2-methyl-2', 4'-diamino-azobenzene.

Example 2 4.1 g. of '2 c hloraniline *(o chloraniline) were dissolved 'in 150 'cc. 'of water and 10 cc. "of cone.

hydrochloric 'acid. The solutionwas cooled to 2 and 'diazotized with a 10% solution of sodium nitrite, using starch-potassium iodide paper as The resulting diazonium salt solution The acidity'of the mixture was then reduced with'saturated sodium acetate'solution, whereup'on copulation commenced. After three hours saturated sodiumchloride was added, and the "hydrochloride of the dye was precipitated in dark "colored crystalline form. The precipitate was '"oollected,"washed, dissolvedin water and the base was precipitated with sodium hydroxide. The base, when recrystallized from toluene, forms fine orange-yellow colored needles with a melting point of about 125-1260.

The probable-structural formula-10f this compound is:

.2-chloroe2 ,4 -diamino-azobenzene.

Example 3 B-methylaniline (m-toluidine), :when diazotized and coupled with .m-phenylene-diamine,

.formsbead-like .clusters of short,:orange colored needles-which when purified by recrystallization out of toluene, have a 'meltingpoint of about .95-96" .C.

.Thelprobable structural formula of this compound is:

NH: 3H:

:3-methyl-2 ,4 -.diamino-azobenzene.

Example 4 2 g. of 3'-butyl anilinewere dissolvedin cc. of "water and 14 cc. of concentrated hydrochloric acid. The solution was cooled-down=to*5 C.-and

a solutionof l g. of-sodium nitrite in'10'cc. of

water=was addedydrop by drop. After all the sodium nitrite PP solution was added, the mixture was allowed to stand for 15 minutes' andt then a few grams of urea were added to combine with the excess sodium nitrite.

The resulting diazonium salt solution was filtered and a solution of 2.4 g. of metaphenylene diamine hydrochloride in 50 cc. of water'was added. The solution was made almost neutral with saturated sodium acetate solution and copulation then ensued. A red precipitate, the hydrochloride of the dye, deposited. After standing for two hours, the precipitate was collected and washed with water. The hydrochloride of the dye'was then dissolved-in dilute (about 2%) hydrochloric acid, filtered and the base was precipitated with sodium hydroxide. It was purified by recrystallization out of toluene with the formaition of an -or'ange colored crystalline powder,

-having a melting point of about ll-72 C.

Theprobables'tructural formula of this compound is:

NH: C4H9 3-butyl,2,4'-diamino-azobenzene.

Example 5 '3 chloraniline (m-ch1oran'i1ine) when dia'zotize'd and coupled with m-phen'ylene diamine, forms 'yr-llow orange colored plates, which when purified by recrystallization out- 0f toluene,'=ha.ve a melting point of about -'121-1'22-C.

The probable I? structural formula i of this compoundis:

NHa Cl pounds specifically "described herein by way of illustration.

'Allthe compounds above :described show de- "c'i'deli 'bacteriostatic 'and' bactericidal properties,

"when "tested '"by the agar :plate method against Staphylococcus'pyogenes aureus and'Bacillus coli. I

Thebacteriostatic and. bactericidal properties "vary-quantitatively0ver-a-considerablerange. In

bacteriostatic power against Staphylococcus pybgenes aareus 'is 1280,000 and'the "bactericidal action is 1 :'45,000.

In the case of 2-'ch10ro-2 ,4'-diamino 'azoben- "zene the bactericidal poweragainst Staphylococcuspyogenes aureusis 1i24,000 andthat of 3- '"chloro, 2Z4-diamino+azobenzene -is'-1 1 25,000. The

bactericidal "actionof these I compounds against Bacillus-callus less pronounced.

In general, they are more active-against" cocci, than=theyare againsttherod'bacilli. Some of 7 these '"compounds even may be called specific "againstcocei.

"What is claimed is '-1. Asa medicinal substance-amazocompound of the following structural formula:

lllalogen in which a hydrogen atom more adjacent to the azo group than the para position is replaced by a halogen atom.

3. As a medicinal substance, an azo compound of the structural formula:

where the radicle R represents an alkyl group, or halogen.

4. As a medicinal substance, an azo compound of the structural formula:

QJNQ

where the R represents an alkyl group, or halogen. 5. As a medicinal substance, an azo compound of the structural formula:

NHz El 6. As a medicinal substance an azo compound of the structural formula:

RAEMIER R. RENSHAW. EDMOND T. TISZA. BERNARD F. DUESEL. 

